Temporal contribution of Pdgfra+ progenitors to coronary vascular endothelial and periendothelial cells

Abstract

Today, there is still a great clinical need for heart regenerative therapies. Future therapies should be directed by lessons learnt from vessel developmental biology. The coronary vasculature derives its constituents from different origins during its formation. Endothelial and periendothelial cell heterogeneity is partly due to these diverse developmental origins and may acquire specialised functions depending on their origin.

This thesis describes a Pdgfra+ coronary vascular progenitor population and its temporal-spatial relationship to the mesoderm origin, and contribution to mature vascular networks during heart development. Pdgfra+ cardiac CFU-F isolated from the developing heart at different time points displayed different stem cell characteristics, cell morphology and location within the heart. Some Pdgfra+ progenitors derived from the mesoderm. Other origins such as the neural crest contributed to aorta formation during late embryonic stages. A Pdgfra-Nestin hierarchy exists during Pdgfra+ progenitor population differentiation into endothelial cells and pericytes. Pdgfra+ progenitors transit through Nestin expressing cells before differentiating into endothelial cells and pericytes. Nestin+ cell populations are more differentiated than Nestin- populations and can only form endothelial cell tubes without proper pericyte coverage in vivo. Nestin- populations form endothelial tubes with proper pericyte coverage. Pdgfra+ progenitor commitment to coronary vasculature formation occurs during early embryonic time points at E7.5. Maturing vascular networks present in the E18.5 heart derive from the Pdgfra+ progenitors marked at E7.5. In comparison, Pdgfra+ progenitors present within the heart at E8.5 – E14.5 do not contribute significantly to coronary vasculature within the E18.5 heart.

The work conducted for this thesis indicates that only Pdgfra+ progenitor populations from the early embryonic E7.5 heart contribute significantly to coronary vasculature formation during heart development. The Pdgfra+ progenitors differentiate into endothelial cells and pericytes by first transiting through Nestin expressing cells.